Homozygosity mapping coupled with whole-exome sequencing and protein modelling identified a novel missense mutation in in a consanguineous Pakistani family with Leber congenital amaurosis.

Leber congenital amaurosis (LCA) is a rare form of early onset vision loss or blindness due to retinal dystrophy. This condition is characterized by early vision loss, nystagmus and severe retinal dysfunction. To date, genetic studies have reported 19 genes to be associated with autosomal recessive LCA, most of which are involved in the retinal morphology and the physiology of the phototransduction pathway. In the current study, a large consanguineous family segregating congenital blindness was ascertained from the Dera Ismail Khan region of Pakistan. Genetic analysis was performed through genomewide SNP genotyping (for homozygosity-by-descent mapping), whole-exome sequencing (for mutation identification) and Sanger sequencing (for segregation analysis). structural predictions were performed through SWISS-Model (structure prediction) and ClusPro (molecular docking). Molecular investigation of the present LCA family identified a novel homozygous missense mutation p.Asp306Val in gene (NM_000180.3:c.917A>T). In silico structural modelling and interaction studies predicted significant changes in protein folding and interacting residues. The present molecular genetic study further extends the mutational spectrum of in LCA, and its genetic heterogeneity in the Pakistani population. The findings of the computational studies on protein structure and interaction profile predicted pathogenic consequences of p.Asp306Val on GUCY2D function.